1

α-Carbonyl Nucleophiles

Michael and Stork reactionsAldol condensationClaisen condensation

The Michael Reaction

Addition of any β-dicarbonyl compound to any α,β-unsaturated carbonyl compound, in the β position.

Disampaikan oleh : Dr. Sri Handayani 2013

Edited with the trial version of Foxit Advanced PDF Editor

To remove this notice, visit:www.foxitsoftware.com/shopping

2

The Michael Reaction

Addition of any β-dicarbonyl compound to any α,β-unsaturated carbonyl compound, in the β position.

Generic “Michael” addition

“Michael” addition

3

Mechanism of the Michael Reaction

The Stork Enamine Reaction

O OCH2CH2CH

Oa. b. c. H+/H2O

N H

CH2 CH CH

O

4

Mechanism of the Stork Enamine Reaction

Enolates react with carbonyls

5

The Aldol addition and its products

Mechanism of the Aldolreaction

6

The Aldol condensation makes α,β-unsaturated carbonyls

The Aldol intermediate is not always isolated

7

What’s the mechanism?

The mixed Aldol can be a mess

8

Mixed Aldol works if one has no α-hydrogens

Mixed aldol works if enolate is pre-formed

9

The Claisen condensation makes β-keto esters

Mechanism

10

The essential difference between Aldol and Claisen

leaving group

Why the Claisen only happens once: acidity of β-dicarbonyl

11

Mixed Claisen in which one component has no α-hydrogens

Mixed Claisenbetween ketone and ester

Why don’t we get Aldol with ester enolatenucleophile?

pKa ~ 20 pKa ~ 25

12

Mixed Claisen with formic or carbonate ester

Synthesis problem, from cyclohexanone

13

Solution

Synthesis problem, from cyclohexanone

14

Solution

The Dieckmann Condensation: an intramolecular Claisen condensation

15

Mechanism

16

Intramolecular Aldol can give two possible ring sizes

Intramolecular Aldol can give two possible ring sizes

17

Six-membered rings are preferred

18

The Robinson Annulation: Michael Addition, then intramolecular Aldol condensation

19

Retrosynthetic breakdown

Robinson retrosynthesis

20

Retrosynthetic breakdown

Robinson retrosynthesis